Corticosteroid Resistance in Asthma

  • Koichi FukunagaEmail author
Part of the Respiratory Disease Series: Diagnostic Tools and Disease Managements book series (RDSDTDM)


Although inhaled corticosteroid (ICS) is the typical medication for the treatment of asthma worldwide, there are patients who are nonresponsive to the treatment. Patients with GC-resistant asthma show more frequent exacerbation than other asthmatics, and the number of clinical consultations is much higher. It has been recognized in recent years that asthma is not a single disease; it is a syndrome with various phenotypes. The heterogeneity complicates the analysis of the pathology associated with GC resistance. However, the characterization of the inflammatory and immunological phenotypes and the classification into several end types will be crucial for elucidating the mechanism of GC-resistant asthma. Future work on the molecular mechanisms of GC resistance will facilitate the selection of therapeutic drugs according to the pathology of individual patients with refractory asthma resistant to GC treatment.


Asthma Steroid resistant Type 2 innate lymphoid cell Th17 cell 


  1. 1.
    Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131(3):636–45.CrossRefGoogle Scholar
  2. 2.
    Adcock IM, Ford PA, Bhavsar P, Ahmad T, Chung KF. Steroid resistance in asthma: mechanisms and treatment options. Curr Allergy Asthma Rep. 2008;8(2):171–8.CrossRefGoogle Scholar
  3. 3.
    Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–73.CrossRefGoogle Scholar
  4. 4.
    ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med. 2004;170(6):601–5.CrossRefGoogle Scholar
  5. 5.
    Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med. 2011;365(13):1173–83.CrossRefGoogle Scholar
  6. 6.
    Sher ER, Leung DY, Surs W, Kam JC, Zieg G, Kamada AK, et al. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest. 1994;93(1):33–9.CrossRefGoogle Scholar
  7. 7.
    Leung DY, Martin RJ, Szefler SJ, Sher ER, Ying S, Kay AB, et al. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med. 1995;181(1):33–40.CrossRefGoogle Scholar
  8. 8.
    Matthews JG, Ito K, Barnes PJ, Adcock IM. Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients. J Allergy Clin Immunol. 2004;113(6):1100–8.CrossRefGoogle Scholar
  9. 9.
    Kobayashi Y, Mercado N, Barnes PJ, Ito K. Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. PLoS One. 2011;6(12):e27627.CrossRefGoogle Scholar
  10. 10.
    Li JJ, Tay HL, Maltby S, Xiang Y, Eyers F, Hatchwell L, et al. MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity. J Allergy Clin Immunol. 2015;136(2):462–73.CrossRefGoogle Scholar
  11. 11.
    Goleva E, Li LB, Eves PT, Strand MJ, Martin RJ, Leung DY. Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 2006;173(6):607–16.CrossRefGoogle Scholar
  12. 12.
    Li LB, Leung DY, Martin RJ, Goleva E. Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid-resistant asthma. Am J Respir Crit Care Med. 2010;182(7):877–83.CrossRefGoogle Scholar
  13. 13.
    Loke TK, Mallett KH, Ratoff J, O’Connor BJ, Ying S, Meng Q, et al. Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients. J Allergy Clin Immunol. 2006;118(2):368–75.CrossRefGoogle Scholar
  14. 14.
    Hew M, Bhavsar P, Torrego A, Meah S, Khorasani N, Barnes PJ, et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med. 2006;174(2):134–41.CrossRefGoogle Scholar
  15. 15.
    McWilliams T, Wells AU, Harrison AC, Lindstrom S, Cameron RJ, Foskin E. Induced sputum and bronchoscopy in the diagnosis of pulmonary tuberculosis. Thorax. 2002;57(12):1010–4.CrossRefGoogle Scholar
  16. 16.
    Al-Ramli W, Prefontaine D, Chouiali F, Martin JG, Olivenstein R, Lemiere C, et al. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009;123(5):1185–7.CrossRefGoogle Scholar
  17. 17.
    Vazquez-Tello A, Semlali A, Chakir J, Martin JG, Leung DY, Eidelman DH, et al. Induction of glucocorticoid receptor-beta expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines. Clin Exp Allergy. 2010;40(9):1312–22.CrossRefGoogle Scholar
  18. 18.
    Goleva E, Hauk PJ, Hall CF, Liu AH, Riches DW, Martin RJ, et al. Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages. J Allergy Clin Immunol. 2008;122(3):550.e3–9.e3.CrossRefGoogle Scholar
  19. 19.
    McSharry C, Spears M, Chaudhuri R, Cameron EJ, Husi H, Thomson NC. Increased sputum endotoxin levels are associated with an impaired lung function response to oral steroids in asthmatic patients. J Allergy Clin Immunol. 2014;134(5):1068–75.CrossRefGoogle Scholar
  20. 20.
    Liu W, Liu S, Verma M, Zafar I, Good JT, Rollins D, et al. Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma. J Allergy Clin Immunol. 2017;139(5):1548.e4–58.e4.CrossRefGoogle Scholar
  21. 21.
    Morita H, Moro K, Koyasu S. Innate lymphoid cells in allergic and nonallergic inflammation. J Allergy Clin Immunol. 2016;138(5):1253–64.CrossRefGoogle Scholar
  22. 22.
    Tojima I, Kouzaki H, Shimizu S, Ogawa T, Arikata M, Kita H, et al. Group 2 innate lymphoid cells are increased in nasal polyps in patients with eosinophilic chronic rhinosinusitis. Clin Immunol. 2016;170:1–8.CrossRefGoogle Scholar
  23. 23.
    Kabata H, Moro K, Fukunaga K, Suzuki Y, Miyata J, Masaki K, et al. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat Commun. 2013;4:2675.CrossRefGoogle Scholar
  24. 24.
    Liu S, Verma M, Michalec L, Liu W, Sripada A, Rollins D, et al. Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin. J Allergy Clin Immunol. 2018;141(1):257.e6–68.e6.CrossRefGoogle Scholar
  25. 25.
    Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006;11(1):54–61.CrossRefGoogle Scholar
  26. 26.
    Scott HA, Gibson PG, Garg ML, Upham JW, Wood LG. Sex hormones and systemic inflammation are modulators of the obese-asthma phenotype. Allergy. 2016;71(7):1037–47.CrossRefGoogle Scholar
  27. 27.
    Kim HY, Lee HJ, Chang YJ, Pichavant M, Shore SA, Fitzgerald KA, et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med. 2014;20(1):54–61.CrossRefGoogle Scholar
  28. 28.
    Atmar RL, Guy E, Guntupalli KK, Zimmerman JL, Bandi VD, Baxter BD, et al. Respiratory tract viral infections in inner-city asthmatic adults. Arch Intern Med. 1998;158(22):2453–9.CrossRefGoogle Scholar
  29. 29.
    Hansbro NG, Horvat JC, Wark PA, Hansbro PM. Understanding the mechanisms of viral induced asthma: new therapeutic directions. Pharmacol Ther. 2008;117(3):313–53.CrossRefGoogle Scholar
  30. 30.
    Gerke AK, Yang M, Tang F, Foster ED, Cavanaugh JE, Polgreen PM. Association of hospitalizations for asthma with seasonal and pandemic influenza. Respirology. 2014;19(1):116–21.CrossRefGoogle Scholar
  31. 31.
    Wark PA, Johnston SL, Moric I, Simpson JL, Hensley MJ, Gibson PG. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J. 2002;19(1):68–75.CrossRefGoogle Scholar
  32. 32.
    Patel KK, Vicencio AG, Du Z, Tsirilakis K, Salva PS, Webley WC. Infectious Chlamydia pneumoniae is associated with elevated interleukin-8 and airway neutrophilia in children with refractory asthma. Pediatr Infect Dis J. 2010;29(12):1093–8.CrossRefGoogle Scholar
  33. 33.
    Black PN, Scicchitano R, Jenkins CR, Blasi F, Allegra L, Wlodarczyk J, et al. Serological evidence of infection with Chlamydia pneumoniae is related to the severity of asthma. Eur Respir J. 2000;15(2):254–9.CrossRefGoogle Scholar
  34. 34.
    Green BJ, Wiriyachaiporn S, Grainge C, Rogers GB, Kehagia V, Lau L, et al. Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. PLoS One. 2014;9(6):e100645.CrossRefGoogle Scholar
  35. 35.
    Essilfie AT, Horvat JC, Kim RY, Mayall JR, Pinkerton JW, Beckett EL, et al. Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma. Thorax. 2015;70(5):458–67.CrossRefGoogle Scholar
  36. 36.
    Kim RY, Horvat JC, Pinkerton JW, Starkey MR, Essilfie AT, Mayall JR, et al. MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2. J Allergy Clin Immunol. 2017;139(2):519–32.CrossRefGoogle Scholar
  37. 37.
    Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, et al. Role for NLRP3 inflammasome-mediated, IL-1beta-dependent responses in severe, steroid-resistant asthma. Am J Respir Crit Care Med. 2017;196(3):283–97.CrossRefGoogle Scholar
  38. 38.
    Essilfie AT, Simpson JL, Dunkley ML, Morgan LC, Oliver BG, Gibson PG, et al. Combined Haemophilus influenzae respiratory infection and allergic airways disease drives chronic infection and features of neutrophilic asthma. Thorax. 2012;67(7):588–99.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Pulmonary Division, Department of MedicineKeio University School of MedicineTokyoJapan

Personalised recommendations